The current incidence of infection caused by resistant or difficult to control microbes, including both viruses and bacteria, has created a need for newer approaches to controlling such organisms, as well as to treating those already infected.
Among the more difficult infectious agents to control and treat are the viruses. For example, respiratory syncytial virus (RSV) is a major cause of acute respiratory illness in young children admitted to hospitals and the major cause of lower respiratory tract infection in young children. A major obstacle to producing an effective vaccine against such agents as RSV has been the issue of safety. Conversely, the use of immunoglobulins against such viral agents has proven of some value. For example, studies have shown that high-titred RSV immunoglobulin was effective in prophylaxis for RSV infections in animal models. However, immunoglobulins, while highly effective in animals when used prophylactically, were minimally effective when used therapeutically. Thus, the use of antibodies to treat animals, such as humans, without some additional source of therapy may prove relatively ineffective. Consequently, use of antibodies with additional agents might be more useful and the identification of such agents for combination therapy with antibodies is a teaching of the present invention. The present invention solves problems experienced by previous treatment regimens by combining different forms of therapy as a means of treating the disease. For example, treatment with neutralizing antibody alone fails to address concerns over inflammation whereas treatment with anti-inflammatory agents alone fails to check the progress of the virus. Thus, treatment of RSV with steroids, shown in some cases to have little effect when administered systemically rather than topically, is shown herein to have a greater effect when administered systemically along with a potent neutralizing antibody.
Bacteria also present a formidable challenge in the area of disease control and prevention. This is especially true with the rise of nosocomial infections in hospitals and elsewhere and the use of high-titred antibodies in controlling such infections would be a welcomed solution to this problem.
As a result, an alternative approach to microbial therapy has been the development of antibodies, especially neutralizing monoclonal antibodies, with high specific neutralizing activity. One drawback to this route has been the need to produce human antibodies rather than those of mouse or rat and thus minimize the development of human anti-mouse or anti-rat antibody responses, which potentially results in immunopathology.
One alternative approach has been the production of antibodies in which the genes encoding the mouse heavy and light chain variable regions have been coupled to the genes for human heavy and light chain constant regions to produce chimeric, or hybrid, antibodies.
In some cases, mouse CDRs have been grafted onto human constant and framework regions with some of the mouse framework amino acids being substituted for correspondingly positioned human amino acids to provide a “humanized” antibody. [U.S. Pat. Nos. 5,693,761 and 5,693,762].
A humanized anti-RSV antibody with good affinity has been prepared and is currently being marketed.
In addition, a number of other therapeutic agents useful against such viruses as respiratory syncytial virus (RSV), as well as parainfluenza virus (PIV), have made their appearance. However, some of these chemical agents, such as ribavirin, have presented drawbacks. Thus, for example, ribavirin, although currently licensed for therapy of RSV pneumonia and bronchiolitis (Hall et al, N. Engl. J. Med., 308: 1443 (1983); Hall et al., JAMA, 254:3047 (1985), is still of controversial value [see: Ohmit et al, J. Clin. Epidemiol., 49, 963 (1996)] and has to be administered over an 18 hour period daily by aerosol inhalation. In addition, the level of secondary infection following cessation of treatment is significantly higher than in untreated patients.
While the beneficial effects of such known antibodies as palivizumab and RespiGam® (both produced by Medimmune, Gaithersburg, Md.) has been demonstrated, there has yet to be shown a role for such agents as corticosteroids in the therapy of respiratory syncytial virus (RSV) bronchiolitis and pneumonia. While some of the problems may have been due to inconsistencies in the choice and dosage of the steroids utilized, the combination of corticosteroids with antibodies such as those mentioned herein has been shown to greatly reduce viral titers without altering the degree of inflammation. (see Prince et al, J. Inf. Dis., (2000), infra) Thus, the present invention has solved much of the problem by achieving dramatic reduction in lower respiratory infection (LRI) in animals using steroids in combination with a monoclonal antibody against RSV.